Drug polymer complexes

Abstract

This invention relates to polymeric complexes of drugs to be employed as (or in) sustained release-formulations comprising a cationic active agent, and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel when mixed with said active agent. The invention also relates to the manufacture of such sustained release compositions and their many uses. Also included is a molded prosthesis comprising a prosthesis including a sustained release composition comprising a cationic anti-infective and a complexing polymer.

1 . A sustained release composition comprising a cationic active agent, and a polyanionic water-soluble complexing polymer of sufficient molecular weight that it forms a gel when mixed with said active agent.  
     
     
         2 . A composition as in  claim 1  further comprising calcium sulfate.  
     
     
         3 . A composition as in  claim 1  further comprising a mixture of phosphates, which includes tricalcium phosphate.  
     
     
         4 . A composition as in  claim 1  further comprising hydroxyl apatite.  
     
     
         5 . A composition as in  claim 1  wherein said complexing polymer is at least two complexing polymers of different molecular weight.  
     
     
         6 . A composition as in  claim 1  wherein said active agent is an anti-infective selected from the group consisting of gentamicin, azithromycin, clarithromycin, doxycycline, minocycline and lincomycin, clindamycin, amikacin, vancomycin, tobramycin, nystatin, and amphotericin B.  
     
     
         7 . A composition as in  claim 1  wherein said active agent is an anesthetic selected from the group consisting of dibucaine, tetracaine, procaine, etidocaine, bupivacaine, mepivacaine, and prilocaine.  
     
     
         8 . A composition as in  claim 1  wherein said active agent is an opioid/analgesic selected from the group consisting of fentanyl, sufentenil, morphine, methadone, etorphine, levorphanol, levallorphan, butorphenol, buprenorphine, oxycodone, hydromorphone, propoxyphene, naloxone, naltrexone, nalorphine, nalbuphine, nalmefene, codeine, oxymorphone, and dermorphine.  
     
     
         9 . A composition as in  claim 1  wherein said active agent is an anti-tumor agent.  
     
     
         10 . A composition as in  claim 1  wherein said active agent is a CNS agent selected from the group consisting of acepromezine, prochlorperazine, clomipramine, ondansetron, sertraline, doxazosine, chlorpromazine, and atropine.  
     
     
         11 . A composition as in  claim 1  wherein said complexing polymer is selected from the group consisting of dextran sulfate, carboxymethylcellulose, and pentosan sulfate.  
     
     
         12 . A composition as in  claim 1  wherein said complexing polymer is dextran sulfate (Na).  
     
     
         13 . A composition as in  claim 12  wherein said complexing polymer is dextran sulfate (Na) of molecular weight 500,000 or higher.  
     
     
         14 . A composition as in  claim 1  wherein said complexing polymer is carboxymethylcellulose.  
     
     
         15 . A composition as in  claim 1  wherein said complexing polymer is L-carboxymethylcellulose.  
     
     
         16 . A composition as in  claim 1  wherein said complexing polymer is M-carboxymethylcellulose.  
     
     
         17 . A method of treating an infection in a mammal comprising administering to said mammal a sustained release composition comprising a cationic anti-infective and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel with said anti-infective.  
     
     
         18 . A method of treating bone sepsis, joint sepsis, an infected joint prosthesis, a diabetic foot infection, or periodontal disease, in a mammal comprising administering by injection to said mammal a composition comprising active agent selected from the group consisting of gentamicin, azithromycin, clarithromycin, doxycycline, minocycline and lincomycin, clindamycin, amikacin, vancomycin, tobramycin, nystatin, and amphotericin B. and a complexing polymer of sufficient molecular weight that it forms a gel with said anti-infective.  
     
     
         19 . A method of systemically treating an infection in a mammal comprising administering subcutaneously to said mammal a composition comprising active agent selected from the group consisting of gentamicin, azithromycin, clarithromycin, doxycycline, minocycline and lincomycin, clindamycin, amikacin, vancomycin, tobramycin, nystatin, and amphotericin B and a complexing polymer.  
     
     
         20 . A method of regionally blocking nerves or treating localized pain in a mammal comprising administering by injection to said mammal a composition comprising an anesthetic selected from the group consisting of dibucaine, tetracaine, procaine, prilocaine, etidocaine, bupivacaine, mepivacaine, and a complexing polymer.  
     
     
         21 . A method of treating pain in a mammal comprising administering to said mammal a composition comprising an active agent selected from the group consisting of oxycodone, morphine, fentanyl, sufentanil, and hydromorphone, and a complexing polymer.  
     
     
         22 . A method as in  claim 21  wherein said complexing polymer is at least two complexing polymers of different molecular weight.  
     
     
         23 . A method of treating drug addiction in a mammal comprising administering to said mammal a composition comprising an active agent selected from the group consisting of methadone, buprenorphine, naloxone, and naltrexone, and a complexing polymer.  
     
     
         24 . A method of treating cancer in a mammal comprising administering to said mammal a sustained release composition comprising a cationic anti-tumor agent and a polyanionic water soluble complexing polymer.  
     
     
         25 . A molded prosthesis comprising a prosthesis including a sustained release composition comprising a cationic active agent selected from the group consisting of gentamicin, azithromycin, clarithromycin, doxycycline, minocycline and lincomycin, clindamycin, amikacin, vancomycin, tobramycin, nystatin, and amphotericin B., and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel with said active agent.  
     
     
         26 . A method of producing a sustained release gel composition comprising mixing a cationic active agent and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel with said active agent.  
     
     
         27 . A method of producing a sustained release composition comprising mixing a cationic active agent and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel with said active agent, drying the gel, grinding the dried gel to a powder, and suspending the powder in a suspending agent.  
     
     
         28 . A method of producing a sustained release composition comprising mixing a cationic active agent and a polyanionic water soluble complexing polymer of sufficient molecular weight that it forms a gel with said active agent, and adding calcium sulfate to the gel.  
     
     
         29 . A method as in  claim 28  wherein the calcium sulfate is calcium sulfate hemihydrate.  
     
     
         30 . A method as in  claim 28  wherein the calcium sulfate is calcium sulfate dihydrate.  
     
     
         31 . A composition comprising a mixture of at least two polymer-drug complexes each of which contains a distinct active ingredient.  
     
     
         32 . A composition comprising a solid polymer drug complex suspended in a liquid polymer-drug complex.  
     
     
         33 . A composition comprising a polymeric anion with a poorly soluble cationic drug complex of low molecular weight.  
     
     
         34 . A composition comprising a neutral drug entrapped within a cross-linked reaction product of a polymeric anion and a cation cross-linking agent.